Process for producing optically active carbinols

ABSTRACT

The present invention relates to a process for producing optically active halomethyl phenyl carbinols of the formula (1), comprising reducing halomethyl phenyl ketones of the formula (2) using an asymmetric reducing agent obtained from boranes and optically active α-phenyl-substituted-β-amino alcohols of the formula (3) or optically active α-non-substituted-β-amino alcohols of the formula (4). 
     The present invention further relates to a process for producing optically active carbinols, comprising reacting a prochiral ketone with, an asymmetric reducing agent obtained from optically active β-amino alcohols of the formula (5), a metal boron hydride and Lewis acid or lower dialkyl sulfuric acid. All of the formulas (1) to (5) are the same as shown in the specification.

This application is a divisional of application Ser. No. 08/549,399,filed on Oct. 27, 1995, now U.S. Pat. No. 5,831,132, the entire contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a process for producing opticallyactive carbinols. More particularly, it relates to a process forproducing optically active carbinols, comprising reducing halomethylphenyl ketones using an asymmetric reducing agent.

RELATED PRIOR ART

As a conventional process for producing optically active carbinols, forexample, there has been known a process for producing optically activehalomethyl phenyl carbinols, comprising reducing halomethyl phenylketones using an asymmetric reducing agent obtained from borane andoptically active 2-amino-3-methyl-1,1-diphenylpentan-1-ol whereinhydrogen atoms on the α-position of β-amino alcohol are substituted bytwo phenyl groups.

In this process carbinols having a high optical purity, i.e. 83% eecarbinol and 96% ee carbinol can be obtained from bromomethyl phenylketone and chloromethyl phenyl ketone, respectively, [e.g. J. Chem. Soc.PERKIN TRANS. I., 2039 (1985)].

However, when using the asymmetric reducing agent obtained from thisβ-amino alcohol, there arises such an industrial problem that, when theβ-amino alcohol and objective carbinols are separated by the treatmentwith an acid, a salt which is slightly soluble to water is formed,thereby requiring a complicated post treatment step such as a filteringprocess.

It has also been known that, when methyl phenyl ketone is reduced usingoptically active 2-amino-3-methylbutan-1-ol containing no substituent atthe α-position in place of the above optically active amino alcoholwherein hydrogen atoms on the α-position are substituted by two phenylgroups, the optical purity of the product is drastically decreased from95% ee to 49% ee [e.g. J. Chem. Soc. PERKIN TRANS. I., 2039 (1985)].Thus it, has been believed that, when halomethyl phenyl ketone isreduced using optically active α-phenyl-substituted-β-amino alcoholscontaining only one phenyl group at the α-positions, a product having andrastically low optical purity is similarly obtained.

It has been known that, when bromomethyl phenyl ketone among halomethylphenyl ketones is reduced, the optical purity is decreased by 10% ormore in comparison with the case that chloromethyl phenyl ketone isreduced, as described above. It has been believed that, when bromomethylphenyl ketone is reduced, a product having a lower optical purity ismerely obtained.

On the other hand, in the production of optically active carbinols byasymmetric reduction reactions, there has been desired an industriallyadvantageous process using a reducing agent which is easily available inthe industrial scale and is less expensive. In addition, there has beenproposed a process using a metal boron hydride which is less expensiveand is easily available, industrially, as a hydrogen resource, i.e.process for producing optically active carbinols, comprising reactingprochiral ketones with an asymmetric reducing agent obtained from2-substituted oxazaborolidine containing a substituent on boron, metalboron hydride and acid (Japanese Laid-Open Patent Publication No7-109231). However, according to this process, the optical purity of theresulting optically active carbinols is not necessarily satisfactory,and an improvement in this respect has been desired.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors have intensivelystudied asymmetric reducing agents obtained from β-amino alcohol inorder to find an advantageous process for producing optically activecarbinols. As a result, it has been surprisingly found that anasymmetric reducing agent obtained from reacting boranes with specificβ-amino alcohol, i.e. α-phenyl-substituted-β-amino alcohols containingone phenyl group at the α-position, and makes the post treatment afterthe reaction simple and affords optically active halomethyl phenylcarbinols having a high optical purity. Various studies were conductedin this regard, thus such that present invention has been accomplished.

In addition, the present inventors have intensively studied the aboveissues in order to produce optically active alcohols having a higheroptical purity using a metal boron hydride. As a result, it has beenfound that, when using a specific asymmetric reducing agent obtainedfrom an optically active β-amino alcohol, metal boron hydride and Lewisacid or lower dialkyl sulfuric acid, optically active carbinols having ahigher optical purity can be obtained. Various studies were conducted inthis regard such that the-present invention has been accomplished.

That is, the present invention provides an industrially excellentprocess for producing optically active halomethyl phenyl carbinols ofthe formula (1): ##STR1## wherein X is a chlorine atom or bromine atom;R¹, R² and, R³ independently represent a hydrogen atom, halogen atom, alower alkyl group or a lower alkoxy group; and * means an asymmetriccarbon, comprising reducing halomethyl phenyl ketones of the formula(2): ##STR2## wherein X, R¹, R² and R³ are the same as defined above,using an asymmetric reducing agent obtained from boranes and eitheroptically active α-phenyl-substituted-β-amino alcohols of the formula(3): ##STR3## wherein R⁴ represents an alkyl group having 1 to 6 carbonatoms; R⁵ and R⁶ independently represent a hydrogen atom, a lower alkylgroup or a lower alkoxy group; R⁷ represents a hydrogen atom, a loweralkyl group or an optionally substituted aralkyl group; and * means anasymmetric carbon, or optically active α-nonsubstituted-β-amino alcoholsof the formula (4): ##STR4## wherein R⁸ represents an alkyl group having1 to 6 carbon atoms, an aryl group which is optionally substituted witha lower alkyl group or a lower alkoxy group, or an aralkyl group whichis optionally substituted with a lower alkyl group or a lower alkoxygroup; R⁹ represents a hydrogen atom, a lower alkyl group or anoptionally substituted aralkyl group, or R⁹ and R⁸ bond together torepresent a lower alkylene group; and * means an asymmetric carbon.

In addition, the present invention also provides an industriallyexcellent process for producing optically active carbinols, comprisingreacting prochiral keytone with an asymmetric reducing agent obtainedfrom optically active β-amino alcohols of the formula (5): ##STR5##wherein R¹⁰ represents a hydrogen atom, a lower alkyl group or anoptionally substituted aralkyl group; R¹¹, R¹², R¹³ and R¹⁴independently represent a hydrogen atom, a lower alkyl group, anoptionally substituted aryl group or an optionally substituted aralkylgroup, R¹³ and R¹⁴ are not the same, R¹⁰ and R¹⁴ may bond together torepresent a lower alkylene group and R¹² and R¹³ may bond together torepresent an optionally substituted lower alkylene group; and * means anasymmetric carbon, a metal boron hydride and Lewis acid or lower dialkylsulfuric acid.

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

Process for producing optically active halomethyl phenyl carbinols (1)using an asymmetric reducing agent obtained from boranes and β-aminoalcohols (3) or (4)

X in the halomethyl phenyl ketones represented by the formula (2)represents a chlorine atom or a bromine atom, preferably bromine atom.

Examples of R¹, R² and R³ include hydrogen atom; halogen atoms such asfluorine, chlorine, bromine, etc.; lower alkyl groups such as methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, etc.;lower alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, etc.

Typical examples of the halomethyl phenyl ketones (2) wherein X is abromine atom include 2-bromoacetophenone, 2-bromo-3'-chloroacetophenone,2-bromo-3'-bromoacetophenone, 2-bromo-3'-fluoroacetophenone,2-bromo-3'-methylacetophenone, 2-bromo-3'-ethylacetophenone,2-bromo-3'-propylacetophenone, 2-bromo-3'-butylacetophenone,2-bromo-3'-methoxyacetophenone, 2-bromo-3'-ethoxyacetophenone,2-bromo-3'-propoxyacetophenone, 2-bromo-3'-butoxyacetophenone,2-bromo-4'-chloroacetophenone, 2-bromo-4'-bromoacetophenone,2-bromo-4'-fluoroacetophenone, 2-bromo-4'-methylacetophenone,2-bromo-4'-ethylacetophenone, 2-bromo-4'-propylacetophenone,2-bromo-4'-butylacetophenone, 2-bromo-4'-methoxyacetophenone,2-bromo-4'-ethoxyacetophenone, 2-bromo-4'-propoxyacetophenone,2-bromo-4'-butoxyacetophenone, 2-bromo-2'-chloroacetophenone,2-bromo-2'-bromoacetophenone, 2-bromo-2'-fluoroacetophenone,2-bromo-2'-methylacetophenone, 2-bromo-2'-ethylacetophenone,2-bromo-2'-propylacetophenone, 2-bromo-2'-butylacetophenone,2-bromo-2'-methoxyacetophenone, 2-bromo-2'-ethoxyacetophenone,2-bromo-2'-propoxyacetophenone, 2-bromo-2'-butoxyacetophenone,2-bromo-2'-chloro-3'-methoxyacetophenone,2-bromo-2'-bromo3'-methoxyacetophenone,2-bromo-2'-fluoro-3'-methoxyacetophenone,2-bromo-3'-methoxy-2'-methylacetophenone,2-bromo-2',3'-dimethoxy-acetophenone,2-bromo-2'-ethoxy-3'-methoxyacetophenone,2-bromo-2',3'-dichloroacetophenone,2-bromo-2'-bromo-3'-chloroacetophenone,2-bromo-3'-chloro-2'-fluoroacetophenone,2-bromo-3'-chloro-2'-fluoroacetophenone,2-bromo-3'-chloro-2'-methylacetophenone,2-bromo-3'-chloro-2'-methoxyacetophenone,2-bromo-3'-chloro-2'-ethoxyacetophenone,2-bromo-3'-bromo-4'-chloroacetophenone,2-bromo-2',4'-dibromoacetophenone,2-bromo-2'-bromo-4'-fluoroacetophenone,2-bromo-2'-bromo-4'-methylacetophenone2-bromo-2'-bromo-4'-methoxyacetophenone,2-bromo-4'-chloro-2'-fluoroacetophenone,2-bromo-2',4'-difluoroacetophenone,2-bromo-4'-bromo-2'-fluoroacetophenone,2-bromo-2'-fluoro-4'-methylacetophenone,2-bromo-2'-fluoro-4'-methoxyacetophenone,2-bromo-4'-ethoxy-2'-fluoroacetophenone,2-bromo-4'-chloro-2'-ethoxyacetophenone,2-bromo-4'-bromo-2'-ethoxyacetophenone,2-bromo-4'-fluoro-2'-ethoxy-acetophenone,2-bromo-4'-methyl-2'-ethoxyacetophenone,2-bromo-4'-methoxy-2'-ethoxyacetophenone,2-bromo-4',2'-diethoxyacetophenone,2-bromo-4'-chloro-3'-thoxyacetophenone,2-bromo-4'-bromo-3'-ethoxyacetophenone,2-bromo-4'-fluoro-3'-ethoxyacetophenone,2-bromo-3'-ethoxy-4'-methylacetophenone,2-bromo-3'-ethoxy-4'-methoxyacetophenone,2-bromo-3',4'-diethoxyacetophenone,2-bromo-5'-bromo-3'-chloroacetophenone,2-bromo-3',5'-dibromoacetophenone,2-bromo-5'-bromo-3'-fluoroacetophenone,2-bromo-5'-bromo-3'-methylacetophenone,2-bromo-5'-bromo-3'-methoxyacetophenone,2-bromo-5'-bromo-3'-ethoxyacetophenone,2-bromo-3'-chloro-5'-ethoxyacetophenone,2-bromo-3'-bromo-5'-ethoxyacetophenone,2-bromo-5'-ethoxy-3'-fluoroacetophenone,2-bromo-5'-ethoxy-3'-methylacetophenone,2-bromo-5'-ethoxy-3'-methoxyacetophenone,2-bromo-3',5'-dimethoxyacetophenone, 2-bromo-3',5'-diethoxyacetophenone,2-bromo-3',5'-dichloroacetophenone, 2-bromo-3',5'-difluoroacetophenone,2-bromo-2',6'-dichloroacetophenone,2-bromo-2',4',6'-trichloroacetophenone,2-bromo-3',4',5'-trichloroacetophenone, etc

When X is a chlorine atom, for example, compounds analogous to the above2-bromo-substituted compounds may be used wherein 2-chloro replaces2-bromo in the above compounds.

Halomethyl phenyl ketones (2) can be produced, for example, by reactingthe corresponding methyl phenyl ketones (6), wherein R¹, R² and R³ areas defined above, with sulfuryl chloride or bromine. ##STR6##

For example, it is preferred to use methanol as the solvent when methylphenyl ketones (6) are reacted with bromine, thereby producing theobjective bromomethyl phenyl ketones (7), wherein R¹, R² and R³ are asdefined above, in a high yield without forming by-product.

When using ethanol, propanol, etc. as the solvent, a large amount ofby-products such as dibromomethyl phenyl ketone are formed, whichresults in considerable decrease in yield of bromomethyl phenyl ketones(7). ##STR7##

Anhydrous methanol is normally used, and the amount is normally 0.5 to20 parts by weight, preferably 1.5 to 10 parts by weight per one part ofmethyl phenyl ketones (6). The reaction between methyl phenyl ketones(6) and bromine is normally carried out by adding bromine to a methanolsolution of methyl phenyl ketones (6). Bromine is normally used in anamount of 0.5 to 1.2 mole, preferably 0.8 to 0.99 mole per one mole ofmethyl phenyl ketones (6).

The reaction is normally carried out by (i) adding bromine at 20 to 60°C., preferably 30 to 45° C., over about 0.1 to 5 hours, (ii) stirringfor about 0.1 to 3 hours, (iii) adding water in the same amount as thatof methanol, and (iv) followed by stirring for about 0.1 to 3 hours.

The objective product is taken out of the reaction mass by adding waterin at least half amount of methyl phenyl ketones (6) to deposit theobjective product as a solid, followed by filtering-and washing.

The product can be optionally purified by recrystallizing from anorganic solvent such as hexane, heptane, i-propanol, etc.

The present invention is characterized in that the above halomethylphenyl ketones (2) are reduced with an asymmetric reducing agentobtained from optically active α-phenyl-substituted-β-amino alcohols (3)or optically active α-nonsubstituted-β-amino alcohols (4) and boranes.

Examples of R⁴ in the optically active α-phenyl-substituted-β-aminoalcohols (3) include alkyl groups having 1 to 6 carbon atoms, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,pentyl, hexyl, cyclohexyl, etc.

Examples of R⁵ and R⁶ include lower alkyl groups such as methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, etc.; loweralkoxy groups such as methoxy, ethoxy, propoxy, butoxy, etc.

Examples of R⁷ include a hydrogen atom; lower alkyl groups such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,etc.; aralkyl groups which optionally contain a substituent (e.g. C₁ -C₄alkyl, halogen, C₁ -C₄ alkoxy, etc.), such as benzyl, phenylethyl,p-methylbenzyl, etc.

Examples of R⁸ in the optically active α-non-substituted-β-aminoalcohols (4) include alkyl groups having 1 to 6 carbon atoms, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,pentyl, hexyl, etc.; aryl groups which are optionally substituted with alower alkyl group (having 1 to 4 carbon atoms, normally) or a loweralkoxy group (having 1 to 4 carbon atoms, normally), such as phenyl,naphthyl, p-methylphenyl, p-methoxyphenyl, etc.; aralkyl groups whichare optionally substituted with a lower alkyl group (having 1 to 4carbon atoms, normally) or a lower alkoxy group (having 1 to 4 carbonatoms, normally), such as benzyl, phenylethyl, p-methylbenzyl,p-methoxybenzyl, etc.

Examples of R⁹ include a hydrogen atom; lower alkyl groups such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,etc.; aralkyl groups which are optionally substituted with a lower alkylgroup (having 1 to 4 carbon atoms, normally) or a lower alkoxy group(having 1 to 4 carbon atoms, normally), such as benzyl, phenylethyl,p-methylbenzyl, p-methoxybenzyl, etc.

In addition, R⁸ and R⁹ can bond together to represent lower alkylenegroups such as methylene, dimethylene, trimethylene, tetramethylene,etc.

Typical examples of the optically activeα-phenyl-substituted-β-amino-alcohols (3) include norephedrine,2-amino-1-(2-methoxyphenyl)-1-propanol,2-amino-1-(2-ethoxyphenyl)-1-propanol,2-amino-1-(2-propoxyphenyl)-1-propanol,2-amino-1-(2-methylphenyl)-1-propanol,2-amino-1-(2,5-dimethylphenyl)-1-propanol,2-amino-1-(2,5-dimethoxyphenyl)-1-propanol,2-amino-1-(2,5-dimethoxyphenyl)-1-propanol,2-amino-1-(2,5-dipropoxy-phenyl)-1-propanol,2-amino-1-(2-methoxy-5-methylphenyl)-1-propanol,2-amino-1-(4-methoxy-2-methylphenyl)-1-propanol,2-amino-1-(2-ethoxy-5-methylphenyl)-1-propanol,2-amino-1-(2,4-dimethylphenyl)-1-propanol,2-amino-1-(2,4,6-trimethylphenyl)-1-propanol,1-phenyl-2-amino-1-butanol, 1-phenyl-2-amino-1-pentanol,1-phenyl-2-amino-1-hexanol, which are optically active, and N-alkyl- orN-aralkyl-substituted substances thereof.

Typical examples of the optically active α-non-substituted-β-aminoalcohols (4) include valinol, leucinol, alaninol, phenylalaninol,phenylglycinol, prolinol, 2-azetidine methanol, 2-aziridine methanol,2-pyrrolidine methanol, which are optically active, and N-alkyl- orN-aralkyl-substituted substances thereof.

The amount of the optically active α-phenyl-substituted-β-amino alcohols(3) to be used is normally 0.01 to 0.8 mole, preferably 0.02 to 0.25mole, per one mole of the halomethyl phenyl ketones (2). The amount ofthe optically active α-non-substituted-β-amino alcohols (4) to be usedis normally 0.01 to 0.8 mole, preferably 0.02 to 0.25 mole, per one moleof the halomethyl phenyl ketones (2).

Examples of the boranes include diborane, tetraborane, hexaborane,tetrahydrofuran-borane complex, dimethyl sulfide-borane complex, alkylborane, catecol-borane complex, thioxane-borane complex, etc.

The amount of the boranes to be used is normally 0.8 to 2 mole (in termsof boron), preferably 1.0 to 1.5 mole, per one mole of the opticallyactive α-phenyl-substituted-β-amino alcohols (3) or of the opticallyactive α-non-substituted-β-amino alcohols (4), and the amount is in aranges of 0.3 to 2 mole (in terms boron), preferably 0.5 to 1.5 mole,per one mole of the halomethyl phenyl ketones (2).

The production of the asymmetric reducing agent by the reaction betweenthe optically active αphenyl-substituted-β-amino alcohols (3) oroptically active α-non-substituted-β-amino alcohols (4) and boranes isnormally carried out in a solvent.

Examples of the solvent include ethers such as tetrahydrofuran,1,3-dioxane, 1,4-dioxane, 1,3-dioxolane, thioxane, ethylene glycoldimethyl ether, diethylene glycol dimethyl ether, methyl-t-butyl ether,etc.; aromatic solvents such as benzene, toluene, xylene, chlorobenzene,etc.; hydrocarbons such as hexane, heptane, cyclohexane, etc.;halogenated hydrocarbons such as methylene chloride, ethylene chloride,carbon tetrachloride, etc.; and a mixture thereof.

The amount of the solvent is normally 0.5 to 50 parts by weight per onepart of the optically active α-phenyl-substituted-β-amino alcohols (3)or of the optically active α-non-substituted-β-amino alcohols (4). Thereaction temperature is normally -20 to 80° C., preferably 0 to 60° C.The reaction time varies depending on the reaction temperature, but isnormally about 10 minutes to 3 hours.

In the reduction of the halomethyl phenyl ketones (2), the asymmetricreducing agent to be obtained from the optically activeα-phenyl-substituted-β-amino alcohols (3) or optically activeα-non-substituted-β-amino alcohols (4) and boranes may be used afterisolation, but is normally used without isolation.

The reaction is normally carried out by adding halomethyl phenyl ketones(2) or a mixture of halomethyl phenyl ketones and a solvent to a mixtureof the asymmetric reducing agent and solvent, or adding a mixture of theasymmetric reducing agent and solvent to a mixture of halomethyl phenylketones (2) and a solvent.

As the solvent for halomethyl phenyl ketones (2), for example, there arethe same solvents as those described in the preparation process of theasymmetric reducing agent. The amount of the solvent is normally 0.1 to20 parts by weight, preferably 1 to 18 parts by weight, per one mole ofthe halomethyl phenyl ketones (2).

The reaction temperature is normally about -76 to 100° C., preferablyabout 10 to 80° C. The reaction time varies depending on thetemperature, amount of the boranes, optically activeα-phenyl-substituted-β-amino alcohols (3) or optically activeα-non-substituted-β-amino alcohols (4), etc., but is normally about 1 to10 hours.

The objective optically active halomethyl phenyl carbinols (1) can beeasily isolated, for example, by adding an acid (e.g. hydrochloric acid,etc.) to the reaction mass to decompose the reducing agent, optionallydistilling off the solvent, adding an extraction solvent (e.g. toluene,etc.) and an aqueous acid solution (e.g. hydrochloric acid, etc.) toremove an acid salt of the optically active α-phenyl-substituted-β-aminoalcohols (3) or optically active α-non-substituted-β-amino alcohols (4)to the aqueous layer and distilling off the solvent of the organic layerseparated.

In addition, the optically active α-phenyl-substituted-β-amino alcohols(3) or optically active α-non-substituted-β-amino alcohols (4) can berecovered by alkalifying the acid salt thereof removed to the aqueouslayer, extracting with a solvent (e.g. toluene, etc.) and distilling offthe solvent.

The isolated optically active halomethyl phenyl carbinols (1) can alsobe further purified by subjecting to purification means such asdistillation, various chromatographies, etc.

Thus, the objective optically active halomethyl phenyl carbinols (1)have been obtained. Examples of the compounds include bromomethyl phenylcarbinol, bromomethyl-3'-chlorophenyl carbinol,bromomethyl-3'-bromophenyl carbinol, bromomethyl-3'-fluorophenylcarbinol, bromomethyl-3'-methylphenyl carbinol,bromomethyl-3'-methoxyphenyl carbinol, bromomethyl-3'-ethoxyphenylcarbinol, bromomethyl-4'-chlorophenyl carbinol,bromomethyl-4'-bromophenyl carbinol, bromomethyl-4'-fluorophenylcarbinol, bromomethyl-4'-methlphenyl carbinol,bromomethyl-4'-methoxyphenyl carbinol, bromomethyl-4'-ethoxyphenylcarbinol, bromomethyl-2'-chlorophenyl carbinol,bromomethyl-2'-bromophenyl carbinol, bromomethyl-2'-fluorophenylcarbinol, bromomethyl-2'-methylphenyl carbinol,bromomethyl-2'-methoxyphenyl carbinol, bromomethyl-2'-ethoxyphenylcarbinol, bromomethyl-3'-chloro-2'-methoxyphenyl carbinol,bromomethyl-3'-bromo-2'-methoxyphenyl carbinol,bromomethyl-3'-fluoro-2'-methoxyphenyl carbinol,bromomethyl-2'-fluoro-3'-methylphenyl carbinol,bromomethyl-2',3'-dimethoxyphenyl carbinol,bromomethyl-3'-ethoxy-2'-methoxyphenyl carbinol,bromomethyl-2',4'-dichlorophenyl carbinol,bromomethyl-4'-bromo-2'-chlorophenyl carbinol,bromomethyl-2'-chloro-4'-fluorophenyl carbinol,bromomethyl-2'-chloro-4'-methoxyphenyl carbinol,bromomethyl-2'-chloro-4'-methylphenyl carbinol,bromomethyl-2'-chloro-4'-ethoxyphenyl carbinol,bromomethyl-3'-chloro-5'-ethoxyphenyl carbinol,bromomethyl-3'-bromo-5'-ethoxyphenyl carbinol,bromomethyl-5'-ethoxy-3'-fluorophenyl carbinol,bromomethyl-5'-ethoxy-3'-methylphenyl carbinol,bromomethyl-5'-ethoxy-3'-methoxyphenyl carbinol,bromomethyl-3',5'-diethoxyphenyl carbinol,bromomethyl-3∝,5'-dichlorophenyl carbinol,bromomethyl-3',5'-dibromophenyl carbinol,bromomethyl-3',5'-difluorophenyl carbinol,bromomethyl-2',4',6'-trifluorophenyl carbinol,bromomethyl-2',4',6'-trichlorophenyl carbinol,bromomethyl-2',4',6'-tribromophenyl carbinol,bromomethyl-3',4'-dichlorophenyl carbinol,bromomethyl-3',4'-dibromophenyl carbinol,bromomethyl-3',4'-difluorophenyl carbinol, etc., which are opticallyactive.

According to the present invention, there can be produced opticallyactive halomethyl phenyl carbinols (1) which are useful as syntheticintermediates of a remedy for diabetes, a remedy for hyperglycemia, apreventive/remedy for obesity, etc. in high optical purity, fromhalomethyl phenyl ketoens (2) by using an asymmetric reducing agentobtained from boranes and specific β-amino alcohols, such asα-phenyl-substituted-β-amino alcohols (3) containing one phenyl group atthe α-position or α-non-substituted-β-amino alcohols (4) containing nosubstituent at the α-position.

The post treatment after the reaction is simple and, therefore, thepresent invention is also industrially advantageous in this respect.

Process for producing optically active carbinols using an asymmetricreducing agent obtained from optically active β-amino alcohol (5), metalboron hydride and Lewis acid or lower dialkylsulfuric acid

Examples of R¹⁰ in the optically active β-amino alcohols of the formula(5) to be used in the present invention include a hydrogen atom; loweralkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, pentyl, etc.; aralkyl groups whichoptionally contain a substituent such as lower alkyl group (having 1 to4 carbon atoms, normally) or lower alkoxy group (having 1 to 4 carbonatoms, normally), such as benzyl, phenethyl, methylbenzyl, etc.

Examples of R¹¹, R¹², R¹³ and R¹⁴ include hydrogen atoms; lower alkylgroups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, etc.; phenyl; phenyl substituted with thelower alkyl group (having 1 to 5 carbon atoms, normally) as thatdescribed above; phenyl substituted with a lower alkoxy group (having 1to 5 carbon atoms, normally) such as methoxy, ethoxy, propoxy, butoxy,pentoxy, etc.; aryl group which optionally contains a substituent (e.g.C₁ -C₅ alkyl, C₁ -C₅ alkoxy, halogen, etc.), such as 1-naphthyl,2-naphthyl, etc.; aralkyl groups which optionally contain a substituent(e.g. lower alkyl group having 1 to 5 carbon atoms, lower alkoxy grouphaving 1 to 5 carbon atoms, normally), such as benzyl, phenethyl,methylbenzyl, etc.; provided that R¹³ and R¹⁴ are not the same.

Examples of the lower alkylene group formed by bonding R¹⁰ and R¹⁴ toeach other include methylene, dimethylene, trimethylene, tetramethylene,etc. Examples of the lower alkylene group formed by bonding R¹² and R¹³to each other include trimethylene, tetramethylene,1,2,2-trimethyl-1,3-cyclopentylene, etc.

Typical examples of the optically active β-amino alcohol (5) includenorephedrine, ephedrine, 2-amino-1-(2,5-di-methylphenyl)-1-propanol,2-amino-1-(2,5-dimethoxy-phenyl)-1-propanol,2-amino-1-(2,5-diethoxyphenyl)-1-propanol,2-amino-1-(2,5-dipropoxyphenyl)-1-propanol,2-amino-1-(2-methoxyphenyl)-1-propanol,2-amino-1-(-2ethoxyphenyl)-1-propanol,2-amino-1-(2-propoxyphenyl)-1-propanol,2-amino-1-(2-methylphenyl)-1-propanol,2-amino-1-(2-methoxy-5-methylphenyl)-1-propanol,2-amino-1-(4-methoxy-2-methylphenyl)-1-propanol,2-amino-1-(2-ethoxy-5-methyl-phenyl)-1-propanol,2-amino-1-(2,4-dimethylphenyl)-1-propanol,2-amino-1-(2,4,6-trimethylphenyl)-1-propanol,2-amino-1-(1-naphthyl)-1-propanol, 2-amino-1-(2-naphthyl)-1-propanol,2-amino-1,2-diphenylethanol, 2-amino-1,1-diphenyl-3-methyl-1-propanol,2-amino-1,1-diphenyl-4-methyl-1-butanol,2-amino-1,1-diphenyl-3-methyl-1-propanol,2-amino-1,1-diphenyl-1-propanol, 2-amino-1,1,3-triphenyl-1-propanol,2-amino-1,1,2-triphenyl-1-ethanol, 2-amino-3-methyl-1-butanol,2-amino-4-methyl-1-pentanol, 2-amino-1-propanol,2-amino-3-phenyl-1-propanol, 2-amino-2-phenyl-1-ethanol,2-aminocyclohexanol, 3-aminoborneol, etc., which are optically active,and lower N-alkyl- or N-aralkyl-substituted substances thereof,2-pyrrolidine methanol, α,α-diphenyl-2-pyrrolidine methanol, 2-5piperidene methanol, α,α-diphenyl-2-azilidene methanol, 2-azetidinemethanol, α,α-diphenyl-2-azetidiene methanol, etc., which are alsooptically active.

The amount of the optically active β-amino alcohol(5) is normally 0.01to 0.5 mole, preferably 0.02 to 0.4 mole per one mole of prochiralketones.

Examples of the metal boron hydride to be used in the present inventioninclude lithium boron hydride, sodium boron hydride, potassium boronhydride, zinc boron hydride, etc. Among them, sodium boron hydride isnormally used.

The amount of the metal boron hydride is normally 0.3 to 3 mole (interms of borane), preferably 0.5 to 2 mole, per one mole of prochiralketones.

Examples of the Lewis acid to be used in the present invention includezinc chloride, boron trifluoride, aluminum chloride, aluminum bromide,tin tetrachloride, tin dichloride or a mixture thereof.

Examples of the lower dialkyl sulfuric acid are those having 2 to 8carbon atoms, such as dimethyl sulfuric acid, diethyl sulfuric acid,etc.

The amount of the Lewis acid is normally 0.5 to 2.5 chemicalequivalents, preferably 0.8 to 2.2 chemical equivalents, per onechemical equivalent of the metal boron hydride. The amount of the lowerdialkyl sulfuric acid is normally 0.9 to 1.1 mole, preferably 0.95 to1.05 mole , per one mole of the metal boron hydride.

The reaction is normally carried out in a solvent. Examples of thesolvent include ethers such as dioxane, tetrahydrofuran, diglyme,triglyme, 1,3-dioxolane, etc.; sulfides such as dimethyl sulfide,diethyl sulfide, etc.; or a mixture thereof; and a mixture of the abovesolvent or a mixture thereof and hydrocarbons such as benzene, toluene,xylene, chlorobenzene, 1,2-dichloroethane, etc. The amount of thesolvent is normally 1 to 50 parts by weight per one part by weight ofprochiral ketones.

The asymmetric reducing agent can be prepared by adding Lewis acid orlower dialkyl sulfuric acid to a mixture of the optically active β-aminoalcohol (5), metal boron hydride and solvent, or adding the opticallyactive β-amino alcohol (5) after adding Lewis acid or lower dialkylsulfuric acid to a mixture of the metal boron hydride and solvent. Inthis case, Lewis acid or lower dialkyl sulfuric acid may be added as amixture with the solvent.

The preparation temperature of the asymmetric reducing agent is normally-20 to 100° C., preferably 0 to 80° C. It is preferred to maintain atthe same temperature with stirring for about 0.1 to 10 hours afteradding Lewis acid or lower dialkyl sulfuric acid.

Reduction of the prochiral ketones are performed by treating theasymmetric reducing agent with the prochiral ketones, and it ispreferred to add the prochiral ketones to the asymmetric reducing agent.In this case, the prochiral ketones can also be added after mixing witha solvent.

The reduction temperature is normally not higher than 150° C.,preferably in a range of about -20 to 100° C., more preferably in arange of about 0 to 80° C.

The time to add the prochiral ketones is normally about 0.1 to 20 hours.It is preferred to maintain at the same temperature with stirring forabout 0.1 to 10 hours after adding the prochiral ketones.

The proceeding of the reaction can be confirmed by analytical means suchas gas chromatography, etc.

Examples of the prochiral ketones include prochiral ketones representedby the formula (8):

    R.sup.15 --CO--R.sup.16                                    (8)

wherein R¹⁵ and R¹⁶ are different and represent an optionallysubstituted alkyl group, an optionally substituted aryl group or anoptionally substituted aralkyl group. Examples of the optically activecarbinols to be obtained by applying the prochiral ketones (8) to thereaction of the present invention include compounds represented by theformula (9) ##STR8## wherein R¹⁵ and R¹⁶ are as defined above; and * isan asymmetric carbon.

Examples of the alkyl group in R¹⁵ and R¹⁶ include alkyl groups having 1to 6 carbon atoms, which are optionally substituted with a halogen, suchas methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl,chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,tribromomethyl, trifluoromethyl, 2-chloroethyl, 3-chloropropyl,4-chlorobutyl, etc. Examples of the aryl group include phenyl,substituted-phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, etc.Examples of the substituted-phenyl include halogen-substituted phenylsuch as o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dichlorophenyl, etc.; lower alkyl (having 1 to4 carbon atoms, normally)-substituted phenyl such as o-, m- orp-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-,m- or p-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethylphenyl, etc.; lower alkoxy (having 1 to 4 carbon atoms,normally)-substituted phenyl such as o-, m- or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m- or p-propoxyphenyl, etc.;benzyloxy-substituted phenyl such as o-, m- or p-benzyloxyphenyl, etc.;cyano-substituted phenyl such as o-, m- or p-cyanophenyl, etc.

Examples of the aralkyl group include aralkyl groups which optionallycontains a substituent having 7 to 11 carbon atoms, such as benzyl, o-,m- and p-tolylmethyl, o-, m- and p-ethylbenzyl, o-, m- andp-methoxybenzyl, o-, m- and p-ethoxybenzyl, etc.

Typical examples of the prochiral ketones (8) include acetophenone,propiophenone, butyrophenone, 1-acetonaphthone, 2-acetonaphthone,o-methoxyacetophenone, o-ethoxyacetophenone, o-propoxyacetophenone,o-benzyloxyacetophenone, p-cyanoacetophenone, phenylbenzyl ketone,phenyl(o-tolylmethyl) ketone, phenyl(p-tolylmethyl) ketone,phenyl(m-tolylmethyl) ketone, 2-butanone, 2-pentanone, 2-hexanone,2-heptanone, 2-octanone, cyclohexylmethyl ketone, cyclohexylbenzylketone, 2-chloroacetophenone, 2-bromoacetophenone,2-bromo-3'-chloroacetophenone, 2-chloro-3'-chloroacetophenone,2-bromo-3'-bromoacetophenone; 2-bromo-3'-fluoroacetophenone,2-bromo-3'-methylacetophenone, 2-bromo-3'-ethylacetophenone,2-bromo-3'-propylacetophenone, 2-bromo-3'-butylacetophenone,2-bromo-3'-methoxyacetophenone, 2-bromo-3'-ethoxyacetophenone,2-bromo-3'-propoxyacetophenone, 2-bromo-3'-butoxyacetophenone,2-bromo-4'-chloroacetophenone, 2-bromo-4'-bromoacetophenone,2-bromo-4'-fluoroacetophenone, 2-bromo-4'-methylacetophenone,2-bromo-4'-ethylacetophenone, 2-bromo-4'-propylacetophenone,2-bromo-4'-butylacetophenone, 2-bromo-4'-methoxyacetophenone,2-bromo-4'-ethoxyacetophenone, 2-bromo-4'-propoxyacetophenone,2-bromo-4'-butoxyacetophenone, 2-bromo-2'-chloroacetophenone,2-bromo-2'-bromoacetophenone, 2-bromo-2'-fluoroacetophenone,2-bromo-2'-methylacetophenone, 2-bromo-2'-ethylacetophenone,2-bromo-2'-propylacetophenone, 2-bromo-2'-butylacetophenone,2-bromo-2'-methoxyacetophenone, 2-bromo-2'-ethoxyacetophenone,2-bromo-2'-propoxyacetophenone, 2-bromo-2'-butoxyacetophenone,2-bromo-2'-chloro-3'-methoxyacetophenone,2-bromo-2'-bromo-3'-methoxyacetophenone,2-bromo-2'-fluoro-3'-methoxyacetophenone,2-bromo-3'-methoxy-2'-methylacetophenone,2-bromo-2',3'-dimethoxyacetophenone,2-bromo-2'-ethoxy-3'-methoxyacetophenone,2-bromo-2',3'-dichloroacetophenone,2-bromo-2'-bromo-3'-chloroacetophenone,2-bromo-3'-chloro-2'-fluoroacetophenone,2-bromo-3'-chloro-2'-fluoroacetophenone,2-bromo-3'-chloro-2'-methylacetophenone,2-bromo-3'-chloro-2'-methoxyacetophenone,2-bromo-3'-chloro-2'-ethoxyacetophenone,2-bromo-3'-bromo-4'-chloroacetophenone,2-bromo-2',4'-dibromoacetophenone,2-bromo-2'-bromo-4'-fluoroacetophenone,2-bromo-2'-bromo-4'-methylacetophenone,2-bromo-2'-bromo-4'-methoxyacetophenone,2-bromo-4'-chloro-2'-fluoroacetophenone,2-bromo-2'4'-difluoroacetophenone,2-bromo-4'-bromo-2'-fluoroacetophenone,2-bromo-2'-fluoro-4'-methylacetophenone,2-bromo-2'-fluoro-4'-methoxyacetophenone,2-bromo-4'-ethoxy-2'-fluoroacetophenone,2-bromo-4'-chloro-2'-ethoxyacetophenone,2-bromo-4'-bromo-2'-ethoxyacetophenone,2-bromo-4'-fluoro-2'-ethoxyacetophenone,2-bromo-4'-methyl-2'-ethoxyacetophenone,2-bromo-4'-methoxy-2'-ethoxyacetophenone,2-bromo-4',2'-diethoxyacetophenone,2-bromo-4'-chloro-3'-ethoxyacetophenone,2-bromo-4'-bromo-3'-ethoxyacetophenone,2-bromo-4'-fluoro-3'-ethoxyacetophenone2-bromo-3'-ethoxy-4'-methylacetophenone,2-bromo-3'-ethoxy-4'-methoxyacetophenone2-bromo-3',4'-diethoxyacetophenone,2-bromo-51-bromo-3'-chloroacetophenone,2-bromo-3',5'-dibromoacetophenone,2-bromo-5'-bromo-3'-fluoroacetophenone,2-bromo-5'-bromo-3'-methylacetophenone,2-bromo-5'-bromo-3'-methoxyacetophenone,2-bromo-5'-bromo-3'-ethoxyacetophenone,2-bromo-4'-chloro-5'-ethoxyacetophenone,2-bromo-3'-bromo-5'-ethoxyacetophenone,2-bromo-5'-ethoxy-3'-fluoroacetophenone,2-bromo-5'-ethoxy-3'-methylacetophenone,2-bromo-5'-ethoxy-3'-methoxyacetophenone,2-bromo-3',5'-dimethoxyacetophenone, 2-bromo-3',5'-diethoxyacetophenone,2-bromo-3',5'-dichloroacetophenone, 2-bromo-3',5'-difluoroacetophenone,2-bromo-2',6'-dichloroacetophenone,2-bromo-2',4',6'-trichloroacetophenone,2-bromo-3',4',5'-trichloroacetophenone, etc.

After the completion of the reduction reaction, for example, the boranecompound is decomposed by adding an acid (e.g. hydrochloric acid, etc.)to the reaction mass, and the solvent is optionally distilled off. Then,an extraction solvent (e.g. toluene, etc.) and an aqueous solution of anacid (e.g. hydrochloric acid, etc.) are added to the mass to remove anacid salt of optically active β-amino alcohols (5) to an aqueous layer,and then the solvent of the organic layer separated is distilled off toisolate the objective optically active carbinols. In addition, opticallyactive β-amino alcohols (5) can be recovered by alkalifying the aqueouslayer obtained, extracting it with an solvent (e.g. toluene, etc.) andthen distilling off the solvent.

The optically active carbinols thus obtained can be further purified bysubjecting to purification means such as distillation, variouschromatographies, etc.

According to the present invention, there can be produced opticallyactive carbinols which are useful as intermediates of drugs (e.g. remedyfor obesity, remedy for diabetes, etc.) and pesticides in high opticalpurity, even when using a metal boron hydride, which is less expensiveand easily available industrially, as the hydrogen resource.

EXAMPLES

The following Examples further illustrate the present invention indetail, but are not to be construed to limit the scope thereof.

Reference Example 1

3'-Chloroacetophenone (154.6 g) and anhydrous methanol (dried with amolecular sieves 4A) (310 ml) were charged in a flask, and bromine(158.2 g) was added dropwise under stirring at 30 to 45° C. over onehour. After continuous stirring at the same temperature for 10 minutes,water (160 g) was added and the mixture was stirred continuously for onehour.

After cooling to -10° C., the crystal deposited was filtered to give 250g of a solid. This solid was dissolved in heptane (750 g), and theresulting solution was washed twice with water (200 g), dried overanhydrous magnesium sulfate and filtered. Then, the filtrate was cooledto -30° C. and the crystal was filtered and dried to give 212.5 g of2-bromo-3'-chloroacetophenone. It was analyzed by subjecting to gaschromatography. As a result, impurities were not observed, yield 91%.

Example 1

After a shrink tube was subjected to nitrogen substitution, (1S,2R)-(+)-norephedrine (0.032 g) and dried tetrahydrofuran (THF, driedusing molecular sieves 4A) (1 ml) were charged in the shrink tube. Then,a 1M solution of THF-BH₃ (4.5 ml) was added under stirring, and themixture was heated to 45° C. and stirred continuously at the sametemperature for 90 minutes.

Then, a solution of 2-bromo-3'-chloroacetophenone (1 g) obtained aboveand dried THF (20 ml) was added dropwise at the same temperature over175 minutes, followed by continuous stirring at the same temperature for20 minutes. After cooling to 10° C., a 1 M solution of hydrochloric acid(0.5 ml) obtained by diluting concentrated hydrochloric acid withethanol was added slowly in order not to foam.

After the solvent was distilled off under reduced pressure, toluene (200ml) and 7% hydrochloric acid (20 ml) were added to separate the aqueousand organic layers. The organic layer was washed with 7% hydrochloricacid (20 ml) and then with water (20 ml), dried over anhydrous magnesiumsulfate and filtered. The solvent was distilled off to give 0.97 g of(R)-bromomethyl-3'-chlorophenyl carbinol, yield 96%.

The optical purity was determined by subjecting to liquid chromatographyusing an optically active column. As a result, it was 91% ee.

Example 2

According to the same manner as that described in Example 1 except forusing (1R, 2S)-(-)-norephedrine (0.032 g) in place of (1S,2R)-(+)-norephedrine, 0.95 g of (S)-bromomethyl-3'chlorophenyl carbinolwas obtained. The yield was 94.2% and the optical purity was 91% ee.

Example 3

According to the same manner as that described in Example 1 except for(i) using (1S, 2R)-(+)-norephedrine (0.016 g) and a 1M solution ofTHF-BH₃ (4.4 ml), (ii) using 2-bromo-4'-chloroacetophenone (1 g) inplace of 2-bromo-3'-chloroacetophenone, and (iii) adding dropwise asolution of 2-bromo-4'-chloroacetophenone and THF over 400 minutes, 0.95g of (R)-bromemethyl-4'-chlorophenyl carbinol was obtained. The yieldwas 94.2% and the optical purity was 94% ee.

Examples 4 to 6

According to the same manner as that described in Example 1 except forchanging the substrate [halomethyl phenyl ketones (2)] and opticallyactive amino alcohols [α-phenyl-substituted-β-amino alcohols(3)],optically active halomethyl phenyl carbinols (1) were obtained,respectively. The results are shown in Table 1.

Example 7

According to the same manner as that described in Example 1 except forusing (i) 2-bromoacetophenone (1 mmol, 0.199 g) in place of2-bromo-3'-chloroacetophenone, (ii) (1S, 2R)-norephedrine(0.2 mmol, 0.03g), and (iii) 1M solution of THF-BH₃ (2.2 ml, 2.2 mmol), an opticallyactive carbinol was obtained. The results are shown in Table 1.

Examples 8 to 9

According to the same manner as that described in Example 7 except forusing (i) (1S, 2R)-2-amino-1-(2,5-dimethoxy)-1-propanol or (1S,2R)-2-amino-1-(2,5-dimethyl)-1-propanol (0.05 mmol each) in place of(1S, 2R)norephedrine and (ii) 1M solution of THF-BH₃ (1.05 ml, 1.05mmol), optically active carbinols were obtained, respectively. Theresults are shown in Table 1.

Example 10 to 11

according to the same manner as that described in Example 7 except forusing (i) 2-chloroacetophenone (1 mmol, 0.155 g) in place of2-bromoacetophenone, (ii) 95% ethyl sulfide complex (2 mmol, 0.2 ml) inplace solution of THF-BH₃, and (iii) (1S,2R)-norephedrine (0.1 mmol,0.015 g in Example 10) or (0.01 mmol, 0.0015 g in Example 11), opticallyactive carbinols were obtained,. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                                             Optical                                    Example  Optically active purity                                              No. Substrate (2) amino alcohol (3) % ee                                    ______________________________________                                        4      2-Bromo-4'-methoxy-                                                                         (1S, 2R)-norephedrine                                                                         80 (R)                                      acetophenone                                                                 5 2-Bromo-3'-methoxy- (1S, 2R)-norephedrine 76 (R)                             acetophenone                                                                 6 2-Chloro-4'- (1S, 2R)-norephedrine 78 (R)                                    chloroacetophenone                                                           7 2-Bromoacetophenone (1S, 2R)-norephedrine 85 (R)                            8 2-Bromoacetophenone (1S, 2R)-2-amino-1-(2,5- 81 (R)                           dimethoxyphenyl)-1-                                                           propanol                                                                    9 2-Bromoacetophenone (1S, 2R)-2-amino-1- 74 (R)                                (2,5-dimethylphenyl)-                                                         1-propanol                                                                  10 2-Chloroacetophenone (1S, 2R)-norephedrine 82 (R)                          11 2-Chloroacetophenone (1S, 2R)-norephedrine 79 (R)                        ______________________________________                                    

Example 12

After a shrink tube was subjected to nitrogen substitution, (R)-valinol(0.853 mmol, 0.088 g) and dried tetrahydrofuran (THF) (20 ml) werecharged in the shrink tube. Then, a 1M solution of THF-BH₃ (9.4 mmol,9.4 ml) was added under stirring, and the mixture was heated to 45 to50° C. and stirred continuously at the same temperature for 90 minutes.

Then, a solution of 2-bromo-3'-chloroacetophenone (4.28 mmol, 1 g)obtained above and dried THF (20 ml) was added dropwise at the sametemperature over 90 minutes, followed by continuous stirring at the sametemperature for 10 minutes. After cooling to 10° C., a 1 M solution ofhydrochloric acid (2 ml) obtained by diluting concentrated hydrochloricacid with ethanol was added slowly in order not to foam.

After the solvent was distilled off under reduced pressure, toluene (190g) and 7% hydrochloric acid (20 g) were added to separate the aqueousand organic layers. The organic layer was washed with 7% hydrochloricacid (20 g) and then with water (20 g), dried over anhydrous magnesiumsulfate and filtered. The solvent was distilled off to give 0.93 g of(R)-bromomethyl-3'-chlorophenyl carbinol, yield 93%.

The optical purity was determined by subjecting to liquid chromatographyusing an optically active column. As a result, it was 89% ee.

Example 13

According to the same manner as that described in Example 12 except forusing (S)-leucinol (0.853 mmol, 0.1 g) in place of (R)-valinol, 0.94 gof (S)-bromomethyl-3'-chlorophenyl carbinol was obtained.

The yield was 94% and the optical purity was 92% ee.

Examples 14 to 24

According to the same manner as that described in Example 12 changingthe substrate [halomethyl phenyl ketones (2)] and optically active aminoalcohols [optically active α-nonsubstituted-β-amino alcohols (4)],optically active halomethyl phenyl carbinols (1) were obtained. Theresults are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                                           Optical                                      Example  Optically active purity                                              No. Substrate (2) Amino alcohol (4) % ee                                    ______________________________________                                        14     2-Bromoacetophenone                                                                          (R)-valinol  96   (R)                                     15 2-Bromoacetophenone (S)-leucinol 90 (S)                                    16 2-Bromoacetophenone (R)-phenylglycinol 90 (R)                              17 2-Bromoacetophenone (S)-phenylalaninol 84 (S)                              18 2-Bromoacetophenone (R)-alaninol 85 (R)                                    19 2-Bromoacetophenone (S)-pyrrolinol 91 (S)                                  20 2-Bromo-4'-methoxy- (R)-phenylglycinol 88 (R)                               acetophenone                                                                 21 2-Bromo-3'-methoxy- (R)-phenylglycinol 88 (R)                               acetophenone                                                                 22 2-Chloro-2'-4'-di- (S)-leucinol 51 (S)                                      chloroacetophenone                                                           23 2-Chloro-4'-chloro- (S)-valinol 94 (S)                                      acetophenone                                                                 24 2-Bromo-4'-methyl- (S)-leucinol 81 (S)                                      acetophenone                                                               ______________________________________                                    

Example 25

To a mixture of tetrahydrofuran (30 ml) and sodium boron hydride (8.56mmol, 0.334 g), dimethylsulfuric acid (8.56 mmol, 1.102 g) was added at40° C. under a nitrogen flow, and the mixture was stirred continuouslywhile maintaining at 45 to 50° C. for one hour.

Then, a solution of (1S, 2R)-norephedrine (0.856 mmol, 0.1294 g) andtetrahydrofuran (2 ml) was added at the same temperature, followed bycontinuous stirring at the same temperature for 1.5 hours. Then, asolution of 2-bromo-3'-chloroacetophenone (4.28 mmol, 1 g) andtetrahydrofuran (20 ml) was added dropwise over 30 minutes, and themixture was stirred continuously while maintaining at the sametemperature for 0.5 hours.

After the completion of the reaction, the reaction solution was cooledto 10° C. and a hydrochloric acid/methanol solution (concentratedhydrochloric acid was diluted with methanol to prepare a 1 N solution)(85 ml) was added. After stirring one hour, the solvent was distilledoff and toluene (200 ml) and 7% hydrochloric acid (50 ml) were added tocarry out extraction. The organic layer was washed with aqueous sodiumbicarbonate and then with water and dried over magnesium sulfate, andthen the solvent was distilled off to give 0.91 g of(R)-3'-chlorophenylbromomethyl carbinol. The optical purity was 84.6%ee.

Examples 26 to 29

According to the same manner as that described in Example 25 except forusing 4'-phenylacetophenone (4.28 mmol, 0.84 g),3',4'-methylenedioxyacetophenone (4.28 mmol, 0.703 g),3-chloropropyl-p-t-butylphenylketone (4.28 mmol, 1.02 g) or2',4'-dichloroacetophenone (4.28 mmol, 0.809 g) in place of2-bromo-3'-chloroacetophenone, respective optically active carbinols (9)were obtained. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Example                                                                         No. Optically active carbinol (9) Optical yield % ee                        ______________________________________                                        26      (S)-4'-phenylphenylmethyl                                                                        80                                                    carbinol                                                                     27 (S)-3',4'-methylenedioxymethyl 74                                           carbinol                                                                     28 (R)-3-chloropropyl-p-t-butylphenyl 72                                        carbinol                                                                    29 (S)-2',4'-dichlorophenylmethyl 61                                           carbinol                                                                   ______________________________________                                    

Examples 30 to 34

According to the same manner as that described in Example 25 except forusing (S)-leucinol (0.856 mmol, 0.1 g), (R)-phenylglycinol (0.856 mmol,0.117 g), (1S, 2R)-2-amino-1,2-diphenylethanol (0.856 mmol, 0.183 g),(S)-valinol (0.856 mmol, 0.088 g) or(R)-5,5-diphenyl-2-methyl-3,4-propane-1,3,2-oxazaboridine (0.856 mmol,0.237 g) in place of (1S, 2R)-norephedrine, optically active carbinols(9) were obtained. The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Example   Optically active amino alcohols                                                                  Optical yield                                      No. (5) % ee                                                                ______________________________________                                        30        (S)-leucinol       72      (S)                                        31 (R)-phenylglycinol 71 (R)                                                  32 (1S, 2R)-2-amino-1,2-diphenyl 91 (R)                                        ethanol                                                                      33 (S)-valinol 90 (S)                                                         34 (R)-5,5-diphenyl-2-methyl-3,4-pro 87 (R)                                    pane-1,3,2-oxazaboridine                                                   ______________________________________                                    

Examples 35 to 37

According to the same manner as that described in Example 25 except forusing (R)-phenylglycinol (0.856 mmol, 0.117 g) and acetophenone (4.28mmol, 0.514 g) in Example 35, (1S, 2R)-2-amino-1,2-diphenylethanol(0.856 mmol, 0.183 g) and 2-bromo-3'-methoxyacetophenone (4.28 mmol,0.98 g) in Example 36 or (S)-valinol (0.856 mmol, 0.088 g) and2-chloro-4'-chloroacetophenone (4.28 mmol, 0.809 g) in Example 37 inplace of (1S, 2R)-norephedrine and 2-bromo-3'-chloroacetophenone,optically active carbinols (9) were obtained. The results are shown inTable 5.

                  TABLE 5                                                         ______________________________________                                        Example                                                                         No. Optically active carbinol (9) Optical yield % ee                        ______________________________________                                        35     (S)-phenylmethyl carbinol                                                                        96                                                    36 (S)-3'-methoxyphenylbromomethyl 86                                          carbinol                                                                     37 (S)-4'-chlorophenylmethyl 83                                                carbinol                                                                   ______________________________________                                    

Example 38

To a mixture of tetrahydrofuran (10 ml), sodium boron hydride (10 mmol,0.378 g) and (1S, 2R)-norephedrine (1 mmol, 0.151 g), a borontrifluoride-diethyl ether complex (1.5 mmol, 0.18 ml) was added withstirring under a nitrogen flow, and the mixture was stirred continuouslyat 60° C. for one hour. After cooling to room temperature, a borontrifluoride-diethyl ether complex (11.8 mmol, 1.45 ml) was added,followed by heating to 60° C. over one hour.

Then, a solution of 2-bromoacetophenone (10 mmol, 1.991 g) andtetrahydrofuran (5 ml) was added dropwise at the same temperature for 10minutes, followed by continuous stirring at the same temperature for 10minutes.

After the completion of the reaction, 10% hydrochloric acid (10 ml) wasadded under ice cooling, followed by stirring. Then, the reactionsolution was extracted with toluene and the organic layer was washedwith water to give a toluene solution of (R)-2-bromo-1-phenylethanol.The reaction rate was 100% and the optical purity was 79.8% ee.

Example 39

According to the same manner as that described in Example 38 except forusing (1S, 2R)-2-amino-1,2-diphenyl ethanol (1 mmol, 0.2133 g) in placeof (1S, 2R)-norephedrine, a toluene solution of(R)-2-bromo-1-phenylethanol was obtained.

The reaction rate was 100% and the optical purity was 87.4% ee.

What is claimed is:
 1. A process for producing optically activecarbinols, consisting of reacting a prochiral ketone with,(a) anasymmetric reducing agent obtained from optically active β-aminoalcohols of the formula (5) ##STR9## wherein R¹⁰ represents a hydrogenatom, a lower alkyl group or an optionally substituted aralkyl group;R¹¹, R¹², R¹³ and R¹ independently represent a hydrogen atom, a loweralkyl group, an optionally substituted aryl group or an optionallysubstituted aralkyl group, R¹³ and R¹⁴ are not the same, R¹⁰ and R¹⁴ maybond together to represent a lower alkylene group selected from thegroup consisting of dimethylene and trimethylene, R¹² and R¹³ may bondtogether to represent an optionally substituted lower alkylene group;and * is an asymmetric carbon, (b) a metal boron hydride, and (c) Lewisacid or lower dialkyl sulfuric acid, wherein the prochiral ketone is aketone of formula (8):

    R.sup.15 --CO--R.sup.16                                    ( 8)

wherein R¹⁵ and R¹⁶ are different and represent an optionallysubstituted alkyl group, an optionally substituted aryl group or anoptionally substituted aralkyl group, and the resulting optically activecarbinols are of the formula (9): ##STR10## wherein R¹⁵ and R¹⁶ are asdefined above, and * is an asymmetric carbon, wherein the opticallyactive β-amino alcohol of formula (5) is used in an amount of 0.02 to0.4 mole per one mole of the prochiral ketone.
 2. The process accordingto claim 1, wherein is selected from the group consisting of hydrogen,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,pentyl; optionally substituted aralkyl groups selected from benzyl,phenethyl, and methylbenzyl, wherein the aralkyl group is optionallysubstituted with C₁ -C₄ alkyl or C₁ -C₄ alkoxy; wherein R¹¹, R¹², R¹³and R¹⁴ are independently selected from the group consisting of methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl,phenyl; phenyl substituted with C₁ -C₅ alkyl; phenyl substituted withalkoxy selected from methoxy, ethoxy, propoxy, butoxy, and pentoxy;optionally substituted aryl selected from 1-naphthyl, and 2-naphthyl,wherein the aryl group is optionally substituted with C₁ -C₅ alkyl or C₁-C₅ alkoxy; aralkyl groups selected from benzyl, phenethyl, andmethylbenzyl, wherein the aralkyl group is optionally substituted withC₁ -C₅ alkyl or C₁ -C₅ alkoxy.
 3. The process according to claim 1,wherein the boron hydrate metal is used in an amount of 0.3 to 3 mole(in terms of borane) per one mole of prochiral ketones.
 4. The processaccording to claim 1, wherein R¹² and R¹³ are bonded together to form alower alkylene group selected from the group consisting of trimethylene,tetramethylene, and 1,2,2-trimethyl-1,3-cyclopentylene.